Acute myocardial infarction (AMI) is a major cause of mortality and morbidity worldwide. Each year, an estimated 785,000 persons (STEMI 500,000) will have a new AMI in the United States alone and approximately every minute an American will succumb to one (Roger et al., Circulation, 2012, 125: e2-e220). Every sixth man and every seventh woman in Europe will die from myocardial infarction (ESC Guidelines for the management of acute MI in patients presenting with ST-elevation, Eur. Heart J., 2012, 33:2569-2619).
Currently, timely myocardial reperfusion using either thrombolytic therapy or primary percutaneous coronary intervention (PPCI) is the choice therapy for acute ST-segment elevation myocardial infarction (STEMI) patients (Worner et al., Rev Exp Cardiol., 2013, 66: 5-11). These interventions limit myocardial infarct (MI), preserve left-ventricular systolic function and reduce the onset of heart failure.
However, mortality remains substantial in these patients with in-hospital mortality ranging between 6 and 14% (Mandelzweig et al., Eur. Heart J., 2006, 27: 2285-2293).
Furthermore, morbidity remains substantial—MI is the leading cause of chronic heart failure—with about 5 to 6% of patients having a subsequent cardiovascular event by 30 days and re-hospitalisation at 1 year about 2.7%. (Lagerqvist et al., N. Engl. J. Med., 2014, 371:1111-20).
Paradoxically, although myocardial reperfusion is essential for myocardial salvage, providing oxygen and nutrients to the ischemic area comes at a price, as it can in itself induce myocardial injury and cardiomyocyte death—a phenomenon termed “myocardial reperfusion injury”, the irreversible consequences of which include microvascular obstruction and myocardial infarction (Yellow and Hausenloy, N. Engl. J. Med., 2007, 357: 1121-1135). It is estimated that ischemia-reperfusion injury is responsible for approximately 50% of the final infarct area (Yetgin et al., Neth. Heart J., 2010; 28, 389-392). Previous attempts to translate cardioprotective therapies (i.e. antioxidants, calcium-channel blockers and anti-inflammatory agents) for reducing reperfusion injury into the clinic have been unsuccessful (Frohlich et al., Eur. Heart J., 2013, 34:1714-1724). There is currently no approved effective therapy for preventing myocardial reperfusion injury in reperfused-STEMI patients, making it an important residual target for cardioprotection.
Pioneering work in the 1990s first implicated the mitochondrial permeability transition pore (MPTP) as a critical mediator of lethal myocardial reperfusion injury. The opening of the MPTP (a non-selective channel of the inner mitochondrial membrane) in the first few minutes of reperfusion leads to mitochondrial Ca2+ overload, oxidative stress, restoration of a physiological pH, and ATP depletion (Heusch et al, Basic Res Cardiol, 2010, 105: 151-154). These events induce cardiomyocytes death by uncoupling oxidative phosphorylation.
Alterations in membrane proteins by free radicals are among the important factors in the evolution of myocardial reperfusion damage. Large quantities of reactive oxygen species (ROS) lead to overwhelming of the cellular endogenous antioxidant defenses. This causes, among other effects, the peroxidation of lipid membranes and loss of membrane integrity which results in necrosis and cell death (Zweier and Talukder, Cardiovasc Res, 2006, 70: 181-190). Re-introduction of abundant oxygen at the onset of reperfusion evokes a burst of additional toxic oxygen derivatives, including superoxide anion, hydroxyl radical and peroxynitrite, within the first few minutes of reflow. Moreover, oxidative stress also reduces the bioavailability of nitric oxide (vasodilator compound) at reperfusion, and the administration of NO donors is cardioprotective in animal models.
There is presently a need for an effective treatment of reperfusion injury, particularly myocardial reperfusion injury.